Automated DNA synthesizers have made the production of oligodeoxynucleotides a routine laboratory exercise (S. Horvath et al., 154 Methods in Enzymology 314-326 (1987)). The disclosure of this article and of all other articles recited herein are incorporated by reference as if fully set forth herein. Researchers have now turned their attention to the modification of oligonucleotides.
Nucleosides with different substituents on the bases have been used to prepare modified oligonucleotides. See generally F. Seela et al., 71 Helv. Chim. Acta 1813 (1988); J. Haebner et al., 85 P.N.A.S.U.S.A. 1735 (1988). As such, linkers have been developed for the conjugation of oligonucleotides to solid supports, peptides (J. Haralambidis et al., 28 Tet. Let. 5199 (1987)), reporter labels, (M. Urdea et al., 16 J. Nuc. Acids Res. 4937 (1988)) and biotin. Replacement of the internucleotide phosphodiester linkage with phosphorothioate (F. Eckstein, 54 Ann. Rev. Biochem. 367 (1985)), methylphosphonate (P. Miller et al., 25 Biochemistry 5092 (1986)), carbamate (E. Stirchak et al., 52 J. Org. Chem. 4202 (1987)), alkyl phosphotriester (B. Uznanski et al., 26 Chemica Scripta 221 (1986)), or cationic alkylphosphoramidate (R. Letsinger et al., 110 J. Am. Chem. Soc. 4470 (1988)) linkages have been reported.
Attempts to attach oligonucleotides to certain long chain moieties have been reported. See H. Tullis PCT 88-368625/09810 (1988); A. Kabanov et al., 259 FEBS Let. 327 (1990) (article itself not prior art) and R. Letsinger et al., 86 P.N.A.S. USA 6553 (1989). However, the need still exists for a way to more easily link hydrophobic moieties to a wide variety of oligonucleotides. Such compounds are needed to improve and/or modify membrane permeability, nuclease resistance, binding, protein and complementary DNA and RNA isolation techniques, and solubility.